Nobel Prize 2019: How Cells Sense and Adapt To Oxygen Availability

Nobel Prize 2019: How Cells Sense and Adapt To Oxygen Availability

The 2019 Nobel Prize in physiology and medicine is awarded to the trio of scientists – William G. Kaeling, Gregg L. Semenza and Sir Peter J. Ratcliffe for the discovery of sensing and adaptation mechanism of cells to oxygen availability.

We all know how crucial oxygen is for the existence of an organism. It helps to convert the food into a useful energy source, which in turn drives multiple biochemical pathways within the biological system. Though we are acquainted with the importance of oxygen for decades, the basic understanding of how cells acclimatize to the shift in the oxygen levels within an organism is yet to be inferred.

The discovery by the trio of scientists has helped in identifying the underlying molecular machineries playing role in modulating the gene expression in response to changing oxygen levels. The findings have also unveiled how fluctuating oxygen levels alter cellular metabolism and physiological function. It will be very useful in developing new strategies to combat various diseases like cancer, anemia and more.

Oxygen – The Key Player

The conversion of food into the energy source in mitochondria is an oxygen-dependent mechanism. This shows a sufficient level of oxygen is very critical. The evolutionary development has helped in coming up with a unique mechanism that helps in maintaining the sufficient levels of oxygen supply to all cells and tissues. For example – the presence of the Carotid body in the neck region is a remarkable illustration of cellular mechanisms adapting to changing levels of oxygen. These bodies consist of specialized cells which mediate the oxygen levels in hypoxia-like condition. Similar to this another significant mechanism is EPO dependent response to hypoxia conditions. Wherein low levels of oxygen lead to an increase in levels of erythropoietin causing a rise in red blood cell production (A process called erythropoiesis). However, the understanding of how this process is dependent on oxygen was missing. To find that scientists started to study the EPO gene. Some of the results showed that certain genetic elements present next to the EPO gene play a vital role in controlling the levels of oxygen.

Meanwhile, Sir Peter Ratcliffe was also studying the same phenomenon. Later both the research group found that the oxygen sensing mechanism is commonly present in almost all cells and tissues. On the other side, scientist Semenza was trying to unfold the cellular components involved behind this sensing mechanism. He found a protein complex named as Hypoxia Inducible Factor (HIF) which binds to DNA segments in oxygen-dependent manner. Scientists soon purified the respective protein and identified associated transcription factors (HIF-1α and ARNT) mediating the sensing mechanism using HIF.

Demystifying the Role of VHL

The level of HIF-1α is inversely proportional to the oxygen levels. Certain studies showed that under normal circumstance HIF-1α is protected from degradation. However, under hypoxia conditions, the HIF-1α undergoes ubiquitin-dependent degradation in the proteasome. But how ubiquitin binds to HIF-1α in an oxygen-dependent manner was a big mystery. The answer to this name from the finding of scientist William Kaelin when he was studying an inherited genetic disease named Hippel-Lindau’s disease (VHL disease). Families with VHL mutations are considered to have a higher risk of cancers. Further studies showed that cells with VHL mutations exhibited increased expression of hypoxia-regulated genes. However, upon reintroduction of the VHL gene into the cells the condition turns back to the normal. This highlighted a significant relation between VHL and hypoxia. Other similar studies showed that VHL is a crucial part of the protein complex playing role in marking cellular components for degradation in proteasome in a ubiquitin-dependent manner. Thus, a key discovery was made which demonstrated the VHL interaction with HIF-1α and its subsequent degradation in an oxygen-dependent manner.

Oxygen regulating VHL & HIF-1α interaction

Another missing piece in the puzzle of understanding the oxygen sensing mechanism by cells was to understand how changing oxygen levels mediate the interaction between VHL & HIF-1α. Upon further investigation, scientists discovered hydroxylation as a key in the entire process. They discovered that under normal levels of oxygen, two hydroxyl groups are added to HIF-1α at certain sites, a process known as prolyl hydroxylation. This allows VHL to recognize HIF-1α leading to subsequent binding and controlling degradation of HIF-1α in an oxygen-dependent manner. Scientists soon identified the enzymes involved in the hydroxylation process. Later, certain findings also showed that genes involved in the activation of HIF-1α are also regulated by oxygen-dependent hydroxylation.

Unveiling the oxygen sensing mechanism in the organism is breakthrough research due to its wide application. From the adaptive response in muscle during exercise to immune system response in the body, oxygen sensing plays a very critical role in channelizing these biological processes.  Besides this, it also has a significant role to play in a number of diseases such as anaemia, cancer and more. The Noble prize-winning research has led the path for many other scientists and pharmaceutical companies to develop new drugs targeting this oxygen-sensing mechanism.

Antibodies Targeting Influenza Viruses – A Hope for Universal Vaccine

Antibodies Targeting Influenza Viruses – A Hope for Universal Vaccine

For most of us, influenza infection resolves on its own but in many cases, it can have severe outcomes if ignored. Therefore, scientists across the globe are looking for some effective method to prevent influenza infection. Many pieces of research have been carried out where the scientists are developing antibodies to efficiently target the influenza virus.

The major reason for failure in developing an effective treatment method against the influenza virus is its constantly changing nature, wherein new strains develop regularly. So if you had influenza in the past with say strain-A, your body will have antibodies against it. But next time when you are infected again with some other strain of influenza your body will recognize it as new. This is the reason that no universal vaccine is available till now. However, recent research work by Daniel Stadlbauer et.al embarks a new ray of hope for the development of a universal vaccine against the influenza virus.

Antibody Targeting Neuraminidase

There are multiple influenza virus strains that require designing a new vaccine almost every year. This is the reason vaccine shots against flu are needed to be taken every year, unlike any other infection. But imagine what if we have an antibody that can target all these strains? Such an antibody can be used to design a universal vaccine that can target all strains of influenza including, swine and other avian influenza viruses.

There are certain protein molecules on the surface of the virus which help it to enter the host cells or to replicate in the host body. One such protein is ‘Neuraminidase’ which is the center of the present study. The researchers found a unique antibody that targets the conserved region of this protein, eventually blocking the viral replication and preventing the further spread of infection.

Till now, Tamiflu a well-known drug is used for flu treatment which works by targeting neuraminidase. But as discussed earlier, the virus exists in multiple strains due to variability in neuraminidase protein; in such cases, the existing drugs are not that effective. Moreover, the increasing burden of drug resistance is also a cause of concern. The recent finding of a unique antibody capable of targeting multiple influenza strains can help in overcoming the drawbacks of existing treatment methods.

The researchers tested blood samples from flue patients and observed unique behavior. They found that apart from the common activity of antibody against hemagglutinin, there were some other antibodies targeting something else. Upon investigating three of these unknown antibodies, the researchers found that the antibodies were blocking the neuraminidase activity in all types of known flu viruses. Scientists were amazed by results as for the first time some antibodies have shown activity against a wide range of virus subtypes. Otherwise earlier the activity was limited only to the certain subtype of influenza. But in the present study, the antibodies were able to cross between influenza A and influenza B, showing an extensive range of activity.

Antibody – 1GO1 and mice studies

To analyze the effectiveness of antibodies against the severe cases of flu, researchers tested the antibodies in mice. These mice were given a lethal dose of influenza virus before the introduction of antibodies. The results obtained were astonishing as all three antibodies showed positive results with one antibody named-1GO1 capable of protecting against more than 11 strains of influenza (both human and non-human strains)

It is suggested that for effective use of Tamiflu, it should be administered within 24 hours of infection. However, with the help of present antibodies identified, the administration even after 72 hours of infections showed positive results, which is quite remarkable.  Thus, a similar drug based on these antibodies can be designed to treat influenza infection but to do so scientist need to further understand how these antibodies actually interfere in neuraminidase activity.

Structural and functional analyses

To understand the underlying mechanism behind the antibody-based blocking of viral replication, scientists carried out the structural and functional analyses. They mapped the structures of the antibodies bound to neuraminidase. The findings showed that each of the antibodies had a loop-like structure that slides into the active site of neuraminidase just like a stick between the gears. This interferes with the normal functioning of neuraminidase thereby blocking the release of new virus particles from the infected host cells. This further breaks the entire replication cycle important for the spread of infection.

The most noticing part of the findings was the insertion of a loop by antibodies within the conserved active site without contacting the hypervariable regions in the surrounding. This allowed targeting a broad range of neuraminidase in different influenza viruses than any of the earlier methods.

The study reveals that using these antibodies can provide protection from a wide range of influenza virus strains as it targets the conserved regions of the neuraminidase active site. These conserved regions remain almost the same even across the distantly related virus strains. Thus, using these antibodies can help in universal vaccine development against influenza.

Till now, neuraminidase as a target for the vaccine has been ignored for long but the present study highlights its importance. To take this ahead, researchers are working on developing new and improved treatments and vaccines for influenza based on antibody 1G01.

Scientists Help Immune System Find Hidden Cancer Cells

Scientists Help Immune System Find Hidden Cancer Cells

Cancer is a widely studied topic in bioscience research but yet remains to be mostly unknown and difficult to treat. However, the recent developments in cancer research over the past decade have helped the scientific community to come up with effective treatment methods. But still, one of the most common problems faced in treating cancer cells is difficulty in locating them for efficient targeting. Recently, scientists from Yale University have developed a new system that can help our immune system find the hidden cancer cells and kill them. The research has been published in Journal Nature Immunology.

Why this study holds importance?

It is a known fact that there exists a number of immunotherapies for treating cancers. But these therapies have certain shortcomings as they either don’t work on all patients or are inefficient in different cancer types. The major reason behind this is the failure of these therapies in identifying the cancer cells which reduces their effectiveness. This highlights an urgent need for a more targeted approach that can help curb the menace of cancer.

The development of a new system by scientists in the present study is considered to overcome the drawbacks of the earlier immune therapies. Researchers report that upon testing the new system in mice it has shown positive response against the melanoma, triple-negative breast, and pancreatic tumors, even for those tumors which are situated at a distant location from the primary tumor.

“This is an entirely new form of immunotherapy,” said Sidi Chen, senior author.

How the new system – MAEGI works?

The researchers developed a new system to target the cancer cells which combines the viral gene therapy and CRISPR based gene-editing technology. Unlike the traditional method of searching and making edits at the DNA level by incorporation of new genes, the present system uses a much more targeted approach.

The new system named as MAEGI stands for Multiplexed Activation of Endogenous Gene as Immunotherapy. This system works by searching numerous cancer-causing genes, marking their location by mimicking GPS and subsequently intensifying the signal of these locations for precise targeting.

For instance, you can consider that the new system dresses up the tumor cells in a unique manner that can be easily identified by the immune system of our body and eventually eliminate them. For this, the cold tumors cells lacking any immune cells are converted into hot tumors cells which are packed with tons of immune cells.

“And once those cells are identified, the immune system immediately recognizes them if they show up in the future,” Chen said. The new system, in theory, should be effective against many cancer types, including those currently resistant to immunotherapy, he said.

The researchers will be further optimizing this system to make the manufacturing process easier. Once optimization is done it will be subjected to clinical trials in potential cancer patients.

No wonder that cancer is a rising menace in the present world. Though many therapies are available we still need highly effective methods to treat cancer. The development of the immunotherapy-based system has given rise to a ray of hope for a more effective and proficient treatment that not only treats primary tumor cells but also the distant ones. Let’s look forward to this new development and hope for the best outcomes in subsequent clinical trials.

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